Faculty Bibliography

Brain alpha1-adrenoceptors that participate in behavioral activation were mapped in the mouse brain by determining where microinjection of the alpha1-antagonist, terazosin, inhibited behavioral activity in a novel cage test. A total of 5 out of 23 tested regions were shown to be involved including the dorsal pons/locus coeruleus region (DP/LC), the dorsal raphe/periaqueductal gray area (DR/PAG), the vermis cerebellum (CER), the nucleus accumbens (ACC) and the medial preoptic area (MPOA). Injection in the 4th ventricle was also effective perhaps by acting on several of these regions simultaneously. A partial inhibition was obtained from the motor cortex. Coinjection of the alpha1/2-agonist, 6-fluoronorepinephrine (6FNE) but not the alpha2-agonist, dexmedetomidine (DMT) reversed the behavioral inhibition in all regions. It is hypothesized that brain motoric alpha1-receptors elicit behavioral activation by coordinately exciting several monoaminergic, motor and motivational systems

Brain alpha1-adrenoceptors have been shown to be essential for motor activity and movement in mice using intraventricular injection of alpha1-antagonists. To facilitate subsequent neuroanatomical mapping of these receptors, the present study was undertaken to replicate these effects in the rat. Rats were administered the alpha1-antagonist, terazosin, in the absence and presence of the alpha1-agonist, phenylephrine, in the IVth ventricle and were tested for their motor activity responses to an environmental change. Terazosin was found to produce a dose-dependent, virtually complete cessation of behavioral activity that was reversed by coinfusion of phenylephrine. The results could not be explained by sedation. It is concluded that central alpha1-adrenoceptors are essential for behavioral activation in rats as in mice

Currently, most basic and clinical research on depression is focused on either central serotonergic, noradrenergic, or dopaminergic neurotransmission as affected by various etiological and predisposing factors. Recent evidence suggests that there is another system that consists of a subset of brain alpha(1B)-adrenoceptors innervated primarily by brain epinephrine (EPI) that potentially modulates the above three monoamine systems in parallel and plays a critical role in depression. The present review covers the evidence for this system and includes findings that brain alpha(1)-adrenoceptors are instrumental in behavioral activation, are located near the major monoamine cell groups or target areas, receive EPI as their neurotransmitter, are impaired or inhibited in depressed patients or after stress in animal models, and are restored by a number of antidepressants. This 'EPI-alpha(1) system' may therefore represent a new target system for this disorder

The role of brain epinephrine (EPI) in the regulation of motor activity and movement in mice was examined. Blockade of EPI synthesis with i.p. 2,3-dichloro-alpha-methylbenzylamine (DCMB) or LY134046 was found to produce marked behavioral inactivity which could be significantly reversed by intraventricular injection of EPI and by three other alpha(1)-adrenoceptor agonists, norepinephrine (NE), 6-fluoronorepinephrine (6FNE), and phenylephrine (PE), as well as by serotonin (5HT). EPI had the largest effect of these agonists and also was the only one that reversed nondrug-induced inactivity of mice in their home cages during the light phase. The effects of EPI were blocked by coinfusion of an alpha(1)-adrenoceptor antagonist (terazosin) but not of an alpha(2)-(atipamezole) or beta(1) (betaxolol)-blocker. The rank order of maximal behavioral responses to EPI, 6FNE, and PE in DCMB-treated mice was the same as the rank order of their maximal stimulation of hydrolysis of phosphatidylinositol at cloned alpha(1B)-adrenoceptors in cell culture. On the basis of the above findings and of the central distributions of adrenergic neurons and alpha(1)-adrenoceptors, the existence of a central EPI-innervated alpha(1)-adrenergic receptor system is postulated which serves to coexcite or enhance signaling in several monoaminergic brain regions involved in movement and motor activity

It has been shown that a subgroup of alpha1-adrenoceptors are both essential for spontaneous and novelty-induced behavioral activity and play a key role in the hyperactivity produced by stimulant drugs. In order to define which brain areas these motoric alpha1-receptors operate in, we have conducted a series of studies over the past 2 years on the ability of microinjections of the soluble alpha1-antagonist, terazosin, in various brain regions to induce immobility in a novel cage test. A total of 23 brain areas including those implicated in motor activation, circadian rhythm regulation, or having unusually high densities of alpha1-receptors were examined in mice. A total of 4 regions were found to show 'positive' responses to terazosin: the dorsal pons in or near the locus coeruleus (LC), the dorsal raphe (DR), the nucleus accumbens (ACC) and the cerebellum. The IVth ventricle also yielded a strong immobility response probably due to combined action at the dorsal pons and cerebellum. Partial responses were obtained in the corpus striatum, anterior hypothalamus and medial preoptic region. No effect was found in the ventral tegmental area (VTA), substantia nigra, posterior hypothalamus, amygdala, BNST, prefrontal cortex or hippocampus. An increase in motor activity was found in the septum. The locations of these motoric alpha1-receptors in the dorsal pons, DR, ACC and possibly striatum suggests that they elicit behavioral activation by excitation of the 3 chief monoaminergic systems (NE, 5HT and DA)in the brain. In addition, the cerebellum is known to send efferents to the VTA, LC and DR. Other studies have suggested that motoric alpha1-adrenoceptors are innervated by brain epinephrine (EPI) and constitute a distinct neuronal system for coordinated behavioral activation

A series of new findings on brain alpha1-adrenoceptors has confirmed and greatly extended the hypothesis that these receptors play a key role in depressive illness. First, in experiments using either the ivt. injection of the alpha1-antagonist, terazosin, and /or alpha1B-receptor deficient mice, it has been found that central alpha1 receptors are essential for spontaneous, novelty-and stimulant drug-induced behavioral activity. Second, these 'motoric' alpha1-receptors have also been shown to be present and to mediate neuronal excitation in 3 major monoamine-containing brain regions: the dorsal pons in or near the locus coeruleus (LC), the dorsal raphe (DR) and nucleus accumbens as well as in the cerebellum which sends efferents to the LC, DR and ventral tegmental area. Third, the endogenous neurotransmitter at these motoric alpha1 receptors now appears to be EPI, based on studies of the marked immobility effects of PNMT inhibitors and their reversal by central EPI infusion. Fourth, a long-lasting depletion of brain EPI and a desensitization of brain alpha1-receptors involved in the potentiation of cAMP responses and the motor activating effect of the stimulant, modafinil has been found in stress models of depression in animals. And fifth, depressive illness may be associated with a marked 70-75% depletion of CSF EPI, which is reversed by antidepressant treatment, as well as a subsensitivity of central postsynaptic alpha1-receptors involved in the plasma cortisol response to amphetamine and desmethylimipramine. Based on these findings we postulate the existence of an EPI-innervated-alpha1-adrenergic system that regulates behavioral activation by costimulation of NE-, 5HT-and DAergic processes and is impaired both pre-and postsynaptically by stress and depressive illness

These studies show that either central pharmacological blockade or genetic ablation of alpha(1B)-adrenoceptors markedly attenuates the behavioral activation caused by modafinil, implicating these receptors in the drug's action

Brain alpha(1)-adrenoceptors are known to be necessary for motor activity in rodents and have been shown to be altered by stress and corticosteroids but only in biochemical experiments. To determine if the behaviorally coupled receptors are also affected by stress, the present study examined the effect of stress and corticosteroids treatment on the motor activity response to modafinil, a putative alpha(1)-adrenoceptor agonist, which is unique in that it elicits extremely high levels of activity via these receptors. Mice were subjected to various schedules of restraint stress for 1-6 days and were subsequently tested for either modafinil-induced or dopaminergically induced behavioral activity in the home cage using videotape recording. In experiments on corticosteroid treatment, mice received exogenous corticosterone or dexamethasone in the drinking water before and during the stress and were tested for modafinil-induced activity as above. It was found that the stress significantly reduced the response to the drug by the third daily session. Motor responses to dopaminergic agents including apomorphine, amphetamine, dihydrexidine and quinpirole were either not altered or were increased at this time. Treatment of animals with corticosterone or dexamethasone prior to and during stress prevented the behavioral subsensitivity to modafinil. Corticosterone pretreatment markedly suppressed the plasma corticosterone response to the stress. The present results provide further support for the hypothesis that stress produces a selective desensitization or inhibition of motor-related brain alpha(1)-adrenoceptors and that this effect can be prevented by corticosteroid treatment

We have recently shown that brain alpha-1B-adrenoceptors are necessary for all spontaneous and novelty-induced motor activity and movement in the Swiss-Webster mouse (Neuropharmacology 40:254-261, 2001). The present study is part of a ongoing series of experiments to characterize the brain localization, operation and behavioral significance of these motoric receptors. Mice previously implanted with cannula guides in a wide range of brain structures were infused either uni-or bilaterally with the nonselective alpha-1 antagonist, terazosin at 2 nmoles/infusion in 350 nl saline or saline vehicle over 2.5 min and introduced immediately into a 'moderately' novel, freshly cleaned standard mouse cage where they were videotaped for 10 min. Motor activity was scored as either gross movements, head movements or time immobile. Terazosin produced the greatest suppression of activity when infused into the pons in or near the locus coeruleus and IV ventricle (approx 80% inhibition). A substantial but lesser inhibition (approx 60%) was found with infusion in the n. accumbens while substantia nigra and VTA infusions were largely ineffective. The striatum was sensitive to vehicle infusion and could not be assessed with terazosin. Unexpectedly, infusions in the hippocampus and septum facilitated gross movements. The results suggest that alpha 1 receptors that facilitate behavioral activation to novelty are located in the pons and parts of the basal ganglia, and that there appears to be a second population of these receptors in the septum and hippocampus that inhibits behavioral activation